The long QT syndrome (LQT) is a heterogeneous disorder that causes syncope and sudden death from cardiac arrhythmias. The long term goal of project 2 is to define the genetic and physiologic factors that play a role in this disorder. Project 2 contains three subprojects. Project 2.1 Molecular genetics of LQT: In 1991 we mapped a gene for LQT to chromosome 11p15.5. Our preliminary data indicate that at least one additional LQT gene exists. The immediate goal of subproject 2.1 is to identify an additional LQT locus using linkage analysis. If a candidate gene can be identified at a new LQT locus, its candidacy will be tested using mutational analyses. Alternatively, new candidate genes will be identified using molecular genetic techniques. The long term goal of this subproject is to identify a second LQT gene. Project 2.2 Cellular electrophysiology of LQT: LQT may be caused by a defect in myocellular repolarization. The goal of subproject 2.2 is to test this hypothesis by screening for abnormal currents in cardiac myocytes obtained from biopsy specimens of LQT patients. These studies will be facilitated by a genetically defined LQT population; in each patient the LQT gene has been mapped to chromosome 11p15.5. Project 2.3 Regional cardiac electrophysiology of LQT: The mechanism of LQT may involve regional variation in cardiac repolarization. Cardiac repolarization of LQT hearts will be characterized in a genotypically homogeneous population using multilead electrocardiography and intracardiac electrophysiologic studies. This work will define LQT at the molecular, cellular and organ levels and may lead to a mechanistic understanding of the disorder. The long term goal of the work is to develop new strategies for predicting, preventing, and treating LQT.